While there is still conflict regarding the definition of hypertension, it is generally agreed that hypertension is a systolic blood pressure (BP) ≥ 130mm Hg and/or a diastolic BP ≥ 80 mmHg (2017 ACC/AHA Guidelines), while other groups have a higher threshold to define hypertension, 140/90 (ACP/AAFP guidelines). Dr. Cohen reminds that in most patients a BP >140/90 is not acceptable and should be addressed even if they are already on multiple agents.
Bottom line: Hypertension = systolic blood pressure (BP) ≥ 130mm Hg and/or a diastolic BP ≥ 80 mmHg
Essential hypertension, also called primary hypertension, is hypertension without a clear secondary cause, and it is often the result of multiple processes. However, essential hypertension can be thought about in terms of two primary contributory mechanisms, renin-angiotensin-aldosterone system (RAAS)-driven or sympathetic-driven hypertension (Hallow et al 2014 and Guyton et al 1975).
The RAAS-driven mechanism is more likely salt sensitive, and the problem is primarily volume, even if there are no signs of edema. These patients are more likely to benefit from a thiazide diuretic (Maaliki et al 2022).
The alternative is sympathetic driven hypertension, which occurs in people who have a more active fight-or-flight process. Sympathetic-driven hypertension, in pts with more active fight-or-flight response, can be linked to anxiety & may be more susceptible to drugs like caffeine (DeLalio et al 2020). Sympathetic-drive hypertension may be more symptomatic with the pts experiencing headaches and palpitations.
Pts may be exposing themselves to a larger dose of caffeine than they were 10 or 20 years ago. A Starbucks “venti” coffee has 400 mg of caffeine, and that’s not counting extra shots (Starbucks). When asking a patient how much coffee they drink a day, three cups could mean three large drinks from Starbucks totaling over a gram of caffeine, which could be contributing to hypertension especially in sympathetic driven disease (Mesas et al 2011).
Vascular aging resulting in arterial stiffness also contributes to hypertension (Mitchell 2014). This phenomenon is closely linked with salt intake and environmental exposure, as demonstrated by studying the Yanomami tribe, an isolated community without exposure to the western diet or modern life. Members of the Yanomami tribe have minimal salt intake and do not have any increase in blood pressure with age (INTERSALT Trial: Carvalho et al 1998 and Mueller et al 2018). Chronic kidney disease and diabetes are also associated with early vascular aging (Dai et al 2020 and Ryder et al 2020). Recent work by Dr. Cohen suggests that there could be a reciprocal relationship between vascular aging & metabolic conditions, high blood pressure & large artery stiffness are associated with an increased risk of developing diabetes (Cohen et al 2022).
Structural racism continues to drive health disparities & hypertension is no different (Churchwell et al 2020). Racism and the consequences of racist policies like redlining are associated with hypertension. The Jackson Heart Study generated data that showed that racism leads to elevated BP (Forde et al 2020) & low socioeconomic status (SES) during childhood can lead to high BP even after an individual obtains a higher SES (Glover et al 2020). There is also data showing that a transient increase in violent crime can be linked to a rise in BP (Tung et al 2019).
Bottom Line: RAAS-driven & sympathetic-driven HTN are drivers of essential HTN. RAAS-driven is salt sensitive & responds well to thiazide diuretics like chlorthalidone, & sympathetic-driven HTN is often more susceptible to substances like caffeine.
Pts should be treated with all 3 first line agents before second line agents are added. Dr. Cohen talks at more length on choosing an initial blood pressure agent in episode #321. First line agents are (2017 ACC/AHA Guidelines):
Second line agents include other diuretics (loop diuretics like furosemide, K-sparing diuretics like amiloride, & aldosterone antagonists like spironolactone), beta blockers like carvedilol, alpha-1 blockers like prazosin, alpha-2 agonists like clonidine, and direct vasodilators like hydralazine and minoxidil.
Dr. Cohen taught us that citalopram could be considered another second line antihypertensive agent for pts with anxiety; she often reaches for citalopram before thinking about beta blockers. While there is mixed data about the effect of citalopram on blood pressure (Calvi et al 2021), Dr. Cohen finds that citalopram is useful in lowering blood pressure in patients with comorbid treatment resistant hypertension and anxiety. Individual studies of citalopram have shown it to be effective at lowering blood pressure in patients with chronic posttraumatic stress disorder or patients already on amlodipine (Tucker et al 2003 and Fu et al 2015). This could be due to an effect on the sympathetic nervous system; selective serotonin reuptake inhibitors (SSRIs) like citalopram decrease sympathetic control of the heart (Licht et al 2012). Dr. Cohen noted that some of these patients with anxiety and a history of trauma presented to her clinic with borderline elevated metanephrines. This observation is supported by literature showing that children with a history of abuse and adults with PTSD have altered blood chemistry (Pitman et al 2012 and De Bellis et al 1994). Building trust and learning about a history of trauma and/or anxiety may identify patients who would benefit from citalopram.
Bottom line: Start with the 3 first line agents for BP treatment & consider citalopram if your pt has comorbid anxiety.
Dr. Cohen encourages us to have a low threshold for adding a third agent in a patient who is still hypertensive despite already being on two antihypertensive agents. While we want to avoid polypharmacy, using multiple antihypertensive agents at a lower dose can achieve blood pressure control with fewer side effects (Bennett et al 2017). Your patient doesn’t need to be taking three antihypertensive pills to be on three medications, there are triple fixed dose combination pills available that are often inexpensive and covered by insurance, olmesartan-amlodipine-hctz and valsartan-amlodipine-hydrochlorothiazide. Each additional antihypertensive agent can lower blood pressure 5-15 mmHg (Manisty and Hughs 2012). An exception to this rule is spironolactone, the addition of spironolactone to a patient already on maximum tolerated doses of three antihypertensive medications can lead to a 20 mmHg drop in blood pressure (Chen et al 2020). Dr. Cohen avoids prescribing an MRA if the serum potassium is > 4.5 mEq/L in a patient with chronic kidney disease, and the drug insert for spironolactone uses > 5 mEq/L as a threshold (Spironolactone Drug Insert).
When a beta blocker is not otherwise indicated (atrial fibrillation, heart failure with reduced ejection fraction, or migraines), beta blockers should not be used for first line blood pressure control, even if there is a significant contribution from anxiety. Beta blockers can be associated with an elevated cardiac risk; one of Dr. Cohen’s studies (among several other studies in other patient populations) showed that patients with HIV who were treated using a beta blocker as a first line agent had an increased risk of developing major cardiac events (Rethy et al 2021). Patients with anxiety induced hypertension benefit from control of their anxiety with citalopram (Tucker et al 2003 and Fu et al 2015). Dr. Cohen would be more likely to prescribe a clonidine patch or guanfacine over a beta blocker for hypertension linked with anxiety–only the patch, she never prescribes the clonidine in pill form because of high likelihood of nonadherence using drugs dosed multiple times a day coupled with rebound hypertension (Geyskes et al 1979). Guanfacine is also indicated for ADHD (Iwanami et al 2020), so Dr. Cohen uses this for patients with ADHD and hypertension. Prazosin not a very potent antihypertensive medication but is useful for patients with benign prostatic hyperplasia (BPH) and hypertension. While they can be helpful in some patients, Dr. Cohen finds herself stopping beta blockers much more often than prescribing them. When discontinuing beta blockers, they may need to be weaned due to withdrawal precipitated when they are stopped quickly among patients on a moderate or higher dose (Frishman 1987). She suggests weaning off beta blockers by cutting the dose in half every two weeks, and she sometimes uses clonidine patches to help the process. Hydralazine is not a common antihypertensive for Dr. Cohen. By the time someone gets to needing a potent vasodilator like hydralazine or minoxidil, we are likely missing volume overload or another etiology of their hypertension, and they are more likely to benefit from optimization of their diuretic regimen first. Lastly, Dr. Cohen has never prescribed minoxidil and only stopped it.
Are all thiazides created equal? While a recent study conducted in the Department of Veterans Affairs health system found no cardiovascular benefit of switching from hydrochlorothiazide to chlorthalidone (Ishani et al 2022), this study was not in very high risk patients and there seem to have been differences in adherence across the groups, so Dr. Cohen still uses chlorthalidone in many patients with resistant hypertension or hypertension with chronic kidney disease due to its favorable pharmacokinetics; hydrochlorothiazide has a half life of 9-12 hours (Beermann and Groschinsky-Grind 1977), but chlorthalidone’s half life is longer than 40 hours (Riess et al 1977). Practically, this means that someone who takes hydrochlorothiazide in the morning may not have effective salt clearance during their evening meal. Chlorthalidone is available in 25 mg or 50 mg tablets, but it does not divide well, often breaking into uneven pieces. Due to its long half life, patients can take a half-ish-dose one day and the other half-ish-dose the next, or chlorthalidone can be prescribed every other day for a patient who will remember (Chlorthalidone Drug Insert). Chlorthalidone is notoriously hard to compound, but there is a azilsartan-chlorthalidone combo pill (not currently available as a generic). Prescribing practices in countries differ greatly and favor certain drugs, although hydrochlorothiazide is pervasive in America, its prevalence is more a function of clinical inertia than drug superiority (Messerli and Bangalore 2011 and McNally et al 2019). Lastly, don’t forget about indapamide, which is available in 1.25 mg and 2.5 mg long acting formulations.
Bottom Line: Have a low threshold for adding a third agent in a persistently hypertensive patient. Low dose triple combination pills are a great way to lower blood pressure while avoiding side effects, and beta blockers are not great options for blood pressure until after you’ve exhausted first and other second line agents.
Laboratory evaluation for hypertension should include a basic metabolic panel, a lipid profile, and urinalysis looking for proteinuria (2017 ACC/AHA Guidelines). For hard to control hypertension, renin and aldosterone should also be tested. Dr. Cohen’s research of testing and prescribing data from the VA shows that renin and aldosterone are tested in less than 2% of eligible patients, and testing is associated with a 4-fold higher likelihood of initiating MRA therapy (Cohen et al 2021). Episode #386 with Dr. Matt Luther takes a deep dive into primary aldosteronism. Testing for renin and aldosterone doesn’t just uncover primary aldosteronism, suppressed renin with normal aldosterone is a “Liddle-like” syndrome that can be treated with amiloride, typically starting at 5 mg or 2.5 mg if there is fear of hyperkalemia (Monticone, 2018).
Check for sleep apnea in patients with a thick neck, obesity, morning headaches, daytime sleepiness, a history of snoring, and/or witnessed apnea. Good adherence to continuous positive airway pressure (CPAP) is associated with a reduction in blood pressure (Hoshide et al 2022).
Pheochromocytoma is a very rare cause of hypertension (0.2-0.6%), and they tend to cause symptoms like palpitations, headaches, and diaphoresis. Pheochromocytomas lead to plasma metanephrines above 2-3 times the reference range. Borderline elevated plasma metanephrines may indicate a temporary sympathetic surge (e.g., due to stress from an acute hospitalization) or history of trauma (Pitman et al 2012 and De Bellis et al 1994). Don’t order 24h collections, catecholamines, or dopamine that’s not the correct answer in your practice or on the test.
Bottom Line: If they have hard to control blood pressure, you should measure renin and aldosterone levels. It’s probably not a pheochromocytoma, but if you have to (e.g., if they’re symptomatic), order plasma metanephrines.
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should be less than 130/80. I think some guidelines using that threshold of 140/90, it's reasonable depending on the patient.
it's either the RAS-driven mechanism, which is really your volume sensitivity, this is your renin–angiotensin system being on overdrive, meaning that you're most likely more salt sensitive. You most likely have some extra fluid or plasma volume on board, even if you're not seeing edema in somebody, even if you're not seeing signs of ascites. This isn't like the frank, "Oh, I need a nephrologist to help me do a volume exam type of situation." This is just extra volume in their body but in all the hidden places. And then the alternative is this more sympathetically driven hypertension, people who have a little bit more active fight or flight process and that's the people who maybe are a little bit more anxious and say they think that their hypertension may be causing or linked to their anxiety, but not always people who maybe have a little more symptomatic hypertension. That's often the more sympathetically driven people and just people who you can see their hypertension tends to be a little bit more triggered by things besides salt.
It's rare that people don't have a little bit of both, which is why those fixed-dose combination drugs are really fantastic because it gives you a little bit of bang for your buck on all ends. You get a little bit of a vasodilatory effect from your calcium channel blocker, from your angiotensin receptor blocker or ACE inhibitor. You get a little bit of that RAS effect from the ARB/ACE inhibitor or from a thiazide diuretic or a thiazide-like diuretic with those first-line agents. And that's why they're so effective. They target all of this.
s thought to be due to likely the fact that our sodium diets and just our western exposures, probably pollution, probably a lot of other stressors and things in our life that don't exist in that type of a world, contribute to vascular aging and contribute to why we develop hypertension as we get older, and there's also likely upregulation of RAS involved too. So, it's a bit multifactorial. But we know for sure that vascular aging is real. We know that it's accelerated in certain disease states. For example, in chronic kidney disease people have worse vascular aging that's faster at a younger age, this vascular stiffening, especially in their large blood vessels, and that's related to a part of why we see a higher risk of heart disease and progression of chronic kidney disease in many of these patients.
There're the RAS inhibitors, the ACEs, and the ARBs, there's the thiazide diuretics, the calcium channel blockers, and then some of the second line agents, the beta blockers, alpha-blockers, hydralazine.
One of the things I prescribe most in my complex hypertension clinic is citalopram. It's incredibly effective at improving blood pressure, especially labile hypertension, in people in whom there's an anxiety component and many of them didn't realize there was an anxiety component until someone asked them.
Citalopram has more sympathetic effects than other SSRIs do and it tends to be more effective at lowering a lot of this blood pressure lability due to anxiety. So, citalopram specifically happens to be more effective in that space and I've seen it.
We require metanephrines to be two and a half times the upper limit of normal or higher to really consider a diagnosis of pheochromocytoma.
There's a good deal of literature now also showing that structural racism specifically is associated with an elevated stress state and increased risk of hypertension and adverse cardiac effects. So, this is being shown. We're seeing this in a few other disease states as well. But the stress of dealing with certain factors can definitely in itself cause these types of health issues.
Ruling out other factors and making sure there's no severe target organ damage from what they've been experiencing, like getting an echo if appropriate and checking for proteinuria and microalbuminuria, and looking for other secondary causes that could be causing it.
For example, another presentation that masks itself similarly is a suppressed renin hypertensive. This is people who have low renin but normal aldosterone. It's almost like a Liddle-like syndrome, if anyone remembers that from medical school. We get questions on that in our nephrology board exams all the time. But this is a state where people tend to be more salt sensitive. It's a mild aldosterone excess state where you have just enough aldosterone to suppress your renin, but not to cause the aldosterone to hang out being high. Basically, the person's thinking that they're constantly volume depleted. That's how their body is behaving because of that abnormality of that excess aldo state with the suppressed renin. And so, in those individuals, they tend to be incredibly responsive to diuretic therapy. Often, they're already on a thiazide. It's not enough, and we have to add an additional agent. So, last time I talked about how I love adding amiloride in folks like that or adding a mineralocorticoid receptor antagonist. So, they also can present just like that with those paroxysmal hypertensive types of states. But typically, I'll check for that and when it's not abnormal and we talk more and I learn more about the person and start asking more about their social history and the things they're dealing with in life, we get down to figuring out that there's something deeper going on.
Sympathetic phenotype
And then the other one is this, maybe they have low renin, normal aldo.
Amiloride: start at 5 mg depending on where the person's blood pressure is. If I'm worried about hyperkalemia risk, I might start even at a half tablet at 2.5 mg, but it's only available in 5 mg tablets actually. You can give 5 mg or 10 using two tablets, but you can also do a mineralocorticoid receptor antagonist in those folks too. Either way, amiloride tends to be a little better tolerated than spironolactone in men because of the lack of gynecomastia risk. But now that eplerenone is increasingly more affordable, then any of those are great options for this scenario. I just find amiloride tends to be a little more potent. So, in my really severe uncontrolled patients coming in, I go for that.
56-year-old woman, blood pressure is high. she's on a calcium channel blocker and an angiotensin receptor blocker, a long-acting one, olmesartan, but she's still high. So, what might be your next steps in someone like this? Now we're starting to think, like, do we need to add another agent? What else should we do here to troubleshoot this?
Yeah, so she hasn't yet proven herself as resistant hypertensive because she isn't hypertensive on three anti-hypertensive medications.
We're going to get her to where she needs to be with one more agent, but we have to go through those motions before we go crazy, because she might just be really volume sensitive and missing that diuretic. In somebody like her, I would have a very low threshold to put her on a three-drug fixed-dose combination, keep her life simple. So, we can do olmesartan, amlodipine, HCTZ, keep her on the same two other drugs. And I would start there and see how she does because some people really do surprise you with how diuretic sensitive they are. I think that thiazide diuretics used to get this bad rap of just not being great antihypertensive drugs and it's not true. They can be incredibly effective. It just depends on who you treat with it them because different folks are more responsive to some agents than others.
There's the olmesartan, amlodipine, hydrochlorothiazide fixed-dose combination, and then there's a valsartan, amlodipine, hydrochlorothiazide fixed-dose combination. I tend to go towards the olmesartan one a bit more because it is a little more potent than valsartan.
I think it's important to add, but that's something that we tend to expect when we're adding a new agent is somewhere in the range of 5 to 15 mmHg improvement. But it's really interesting because the only agent that we really see something quite different than that with is when you add spironolactone as your fourth agent. There are meta-analyses that show that when your fourth agent is now spironolactone that you're adding to those three first-line antihypertensive medications that you get on average of 20 mmHg/9 mmHg decline in BP in several studies.
But let's say they're on four drugs now and you're still seeing that they've got sympathetic hypertension.
That's when I'll start using these more beta-blocking and AV nodal-blocking agents. The reason that I don't do it sooner is because these agents are not proven antihypertensive medications associated with, like, cardiac benefit. If anything, actually using beta blockers, especially as your first three agents in particular, is associated with an elevated risk of congestive heart failure, elevated risk of nuanced cardiovascular disease in several studies. We did an emulated trial, for instance, in HIV patients with incident hypertension and we found that when they were treated with the beta blocker as their first-line agent, they had about a 70% increased risk of developing major cardiac events, about 50% increased risk of developing CHF compared to people started on any of the other true first-line agents. This has been shown in several studies. We should not be using beta blockers in particular as first-line antihypertensive agents. It's so incredibly important to have that on our radar. As a fourth-line agent for appropriate patients, I think if there's a real indication to use it of course, if someone has atrial fibrillation if somebody has migraine headaches and we want to use it for prophylaxis, I think they're fantastic. For anxiety, it's not quite clear if somebody has performance anxiety, yeah propranolol is a great option or a beta blocker. For more generalized anxiety, it's not 100% clear. I do use them sometimes in these patients when it's very clearly a huge anxiety component and you're not getting enough benefit from an SSRI and they're taking, like, benzos that are getting prescribed to them and whatnot? In those patients? Yeah, I'll try to use the throw a beta blocker on. If they're more borderline or I think it's a potential contributing factor but there's more at play, I wait. And I actually will use a clonidine patch or guanfacine before I'll go to a beta blocker or alpha-blocker, because beta blockers I worry about are they really helping with the blood pressure, particularly and alpha blockers tend to increase blood pressure lability and I worry about worsening what's already there. I usually save those for last after I do a central alpha agonist like clonidine or guanfacine. If I do clonidine, though, I only do it in patch form. Absolutely will never do it in pill form because it can cause blood pressure lability because it's so short-acting, its pharmacokinetics are so inconsistent from one person to the next. Even if you're taking your clonidine correctly, then you can still end up with that rebound hypertension between doses. So, I really, really am a huge fan of either using the patch or using guanfacine, which is another central alpha agonist that works exactly the same way as clonidine does.
It's actually FDA indicated also for ADHD treatment. So, my patients who come to me asking if they have to stop their Ritalin, I say, "Hold on, I have a drug free." [laughs] And I try to convince them to stop their ADHD medications and switch them over to guanfacine and I've had quite a few people who've like given me hugs after that. I'm a big fan of central alpha agonists as long as they're long-acting. If they are the shorter-acting ones, they can cause a lot more harm than good.
Re: beta blockers: Yeah, we debate this a lot in the hypertension specialist space because some folks won't stop them if someone's doing well on them. One thing I will say is if they've been on it for a long time and they're on a high dose, you actually have to taper it off, much like clonidine because you can end up with a rebound tachycardia and folks can feel quite bad. And so, I have had a handful of these really anxious patients who are on it because their doc was like, "Oh, I want to use this for your hypertension." And we had trouble weaning it off because they were getting palpitations and anxiety trying to wean it off. So, I actually put them on a clonidine patch to wean them off of it. Matt: Yeah, so you wean off over depending on the dose, I imagine. It's like weeks to months or is it just a couple of weeks? Jordy: Weeks. Yeah, I do weeks, I think I usually cut it in half every two weeks, but it depends on how long and the dose.
So, Joanne comes back to the clinic in a month and her blood pressure is still high. It's 146/92 despite your prescribing three antihypertensive agents from three different classes. So, now that we have this patient on three antihypertensive agents, at what point would you consider calling this resistant hypertension? Jordy: So, first we say that we need somebody to meet the definition of resistant hypertension that they have to be on the optimally tolerated doses. So, whatever your highest tolerated doses of at least three first-line antihypertensive agents and still have an elevated blood pressure. If she is on the optimally tolerated dose of three antihypertensive agents, we've got her on max dose of all three and her blood pressure is still elevated, then I would say this is apparent treatment-resistant hypertension. I would not yet say it's treatment-resistant hypertension. The key word being apparent because we think it most likely is resistant hypertension. She meets the technical definition, but the question is, is it actually resistant hypertension or is it pseudo-resistant hypertension? So, the way that we know that for sure is we have to check a few things. First of all, we have to know, do we trust the blood pressures we're getting? If this was somebody coming into my clinic and just getting an initial triaged blood pressure, I for sure would not be trusting the blood pressure that they are getting. I love my medical assistants, but they are under a ton of pressure to ask 20 questions at the exact same time that they're checking that person's blood pressure. If I was a patient, I would still be stressed out by that line of questioning, and I don't think that my blood pressure would be particularly accurate when they're checking it. I'm a huge fan of bringing the patient back to my office space and doing a true high-quality office reading. What I do is I have the luxury of being in my complex hypertension clinic with having Omron 907 Excel automated office blood pressure devices that were used in SPRINT and ACCORD trials. So, I can just hook it onto my patient and get that perfect research-quality blood pressure. I realizes that's not available everywhere, but technically, really, that's what you need to actually be hitting those guideline level required blood pressures is a really well-done blood pressure. So, this has to be someone actually resting for five minutes before their blood pressure is checked. It has to be somebody with their feet flat on the floor, not sitting on an exam table like myself as a 5'4" woman whose feet dangle like crazy on an exam table. Having your back supported also really hard to do on most exam tables, so at least the broken ones in our clinic. And then on top of that, you need to make sure that their arm is supported about at the level of their heart. I don't know if you've seen, I mean, check a blood pressure recently, but it's pretty hard to even do that in general and often definitely not happening on an exam table. And also, on a lot of the armless chairs that people get their blood pressures checked on in clinic also. So, there are just so many factors contributing. You need to also make sure it's being done on a bare arm. People often will have their winter clothes on and not getting a bare arm blood pressure or they'll do the wise thing of pushing the sleeve up on their arm thinking that they're going to get that great bare arm blood pressure. And instead, you're creating a tourniquet effect that's going to give you a falsely elevated blood pressure. So, so many things we do wrong in checking blood pressure in the clinic. So, either we try to actually do it right and get the average of three high-quality readings using an automated device, not using our horrible ears and our miscalibrated manual blood pressure devices that are hanging on the wall that has been smashed into 15 times by cleaning devices and medical students who are too afraid to be too close to the patient. But instead, we're using these automated validated devices where we can actually get an accurate reading. So, all these are incredibly important and if it's not feasible, then we should be getting really good home blood pressures on our patients.
We wrote the meta-analysis showing that the white-coat effect is not associated with elevated cardiovascular risk. We should really not be treating people based off of office readings if they have a white-coat effect, because we could be causing undue side effects from medications and hypotension that the patient doesn't need causing mistrust and causing them to be more likely to have pseudo-resistant hypertension because we think they're taking their meds and they're not.
I mean that's the last case is, nonadherence. So, if people are not taking their medication as prescribed, then they don't really have resistant hypertension. They just are prescribed three antihypertensive medications and are walking around with a high blood pressure. I love the fixed-dose combination tablets because they help to limit this to some extent, but they're not perfect. And it's really hard to know if our patients are being adherent.
We talked about-- this is apparent resistant hypertension. So that was okay. Can we trust the blood pressure? Is there a white-coat hypertension or white-coat effect? And then are they adherent with their medications? Even if they're filling their meds, we still can't be sure they're taking them. Just ask them, what barriers, how can I make it easier for you? Side effects, cost that sort of thing.
. I think absolutely everybody who I am convinced has resistant hypertension should get a renin and aldosterone. We have good evidence to support that, that about 20% of these people have primary aldosteronism and only about 2% of them get tested for primary aldosteronism. That was another one that we actually wrote the literature or one of the papers on that. There are quite a few now just showing that somewhere between 1% and 3% of people get checked. 20% of resistant hypertensive patients have primary aldosteronism. This is treatable and everyone's excuse for why they don't check it is well, it's not going to change my management why should I check it? But then you run into the situation of, well, their kidney disease is getting worse because their primary aldosteronism is probably attacking their kidneys. And then you end up seeing that they can't stay on the MRA anymore. Jordy: You have to decide, am I giving them an MRA or an ARB? It's getting harder to test them because of other complicated issues happening. Test as soon as you have the opportunity so that you don't have to make those hard decisions later. Not to mention, our study actually showed that even though people say that they're starting people on mineralocorticoid receptor antagonists in lieu of testing for primary aldosteronism, but people actually aren't. We looked at 280,000 veterans nationwide and we found that only 14% of people ever over about an 18-year span were started on a mineralocorticoid receptor antagonist even though literally 100% of them had an indication. We excluded anyone without an indication for a mineralocorticoid receptor antagonist. So, 13% were started on one. People who were tested for primary aldosteronism were four to seven times more likely to be started on a mineralocorticoid receptor antagonist than people that were never tested during that 18-year span. So, what that tells us is if you're thinking about testing or thinking about starting it, and a lot of folks are saying, it's not going to change my management, but clearly, you're just not managing it and you're not starting them on the mineralocorticoid receptor antagonist. So, it's all for not you should be testing.
I always will check urinalysis and microalbumin just to make sure we're not missing some occult proteinuria.
What else am I worried about? So, for example, if somebody is more obese, has a thicker neck, or they respond positively to some of the sort of queries I ask about obstructive sleep apnea. Like, do you wake up with morning headaches? Do you feel like you're not well rested? Do you have witnessed apnea? Of course. Then in those folks, I have a low threshold to check for obstructive sleep apnea. We find a lot of it in these patients. Is it going to cure their resistant hypertension to treat it? Not necessarily. But will it help them make them feel a lot better and probably lower their blood pressure a little bit? Yeah. It has been shown that when people actually adhere to the CPAP, we end up seeing a reduction in sympathetic drive during the day, and then you end up seeing an improvement in daytime blood pressures, of course, in addition to nighttime blood pressures. So, I think that there is a lot to be gained by checking for it. And then the other things that we think about are rarer and that I tend to check for less unless I have a specific reason to. Another example is renal artery stenosis, which can be either due to atherosclerotic disease or due to fibromuscular dysplasia. Fibromuscular dysplasia, we tend to diagnose at a younger age, whereas atherosclerotic disease, of course, older people, someone who's got more risk for it. So, somebody who has other atherosclerotic diseases, someone who's a smoker, who's got known hyperlipidemia, those are the folks I'm thinking about atherosclerotic renal artery stenosis in, and even then, I don't push incredibly hard to search for it unless I'm seeing worsening kidney function because the interventions are sometimes worse than the disease. And most of what we can do to help these patients is just medically manage them and make sure they're on a statin, make sure that their blood pressure is under control.
I leave things like pheo for later, because pheochromocytoma, paragangliomas, these are as rare as we think. We do see them, obviously, like our center sees so many of these a year because they get referred to us and we have a whole neuroendocrine center. But it shouldn't be the first thing you're checking for. You should be checking for these other things and then asking yourself, do I have a suspicion for pheo? You don't want to miss it, of course, if somebody has one. But I'm really only checking for it in people with really severe hypertension that's really refractory to treatment and symptomatic hypertension, people with headaches, palpitations, diaphoresis, those types of symptoms, then, of course, I'm searching for it. But it's important, as I'd mentioned earlier, that you're interpreting it correctly. If it's mildly elevated, we don't consider that positive. We really look for 2.5 to 3x the upper limit of normal just for plasma metanephrines as our diagnostic tool for pheochromocytoma. There is not great evidence to support checking 24-hour urine metanephrines. There's really no evidence I'm aware of that really supports screening with urine catecholamines or plasma catecholamines in these patients. Those are tools that we use in research and tools that are used later on to try to nail down specific nuances of the diagnoses. But for some reason, a lot of folks check catecholamines in these patients and just please don't do that. [laughs] Just check plasma metanephrines. That's what the board question is too. [laughs] Matt: So, it's just plasma? Yeah, because sometimes when you order it gives you multiple-- it'll be like epinephrine, normetanephrines. metanephrines. And then you're just looking at the plasma metanephrines and is it greater than two and a half to three times upper limit normal? Jordy: Yeah, and the normetanephrine is part of that too, that comes with it. But you're not looking at like dopamine and there's like a whole other panel of catecholamines that you can get epinephrine and you don't need those.
We know the more common ones, for instance, NSAIDs can increase blood pressure, the degree to which is a little bit controversial. But I do tend to counsel folks that if you can tolerate other agents to try to use non-NSAIDs to manage their pain. But if it's really the only option, I just let them know they're probably going to need additional antihypertensive therapy to treat their blood pressure sort of polypharmacy on top of the NSAIDs. But then there are other drugs, that are a little bit tougher, oral contraceptives with estrogen in them. That's something that's really tough, always a lot of folks really don't always remember that that contributes to hypertension in women. Folks often don't even know if their female patients are on it because it's prescribed by a gynecologist and they're seeing somebody at another center who's their primary care doc and they didn't mention this on their medication list for whatever reason. It's always really important to ask about oral contraceptives and to offer alternative options if someone does have hypertension to rule out that as a contributing factor to their hypertension. So, that's incredibly important to be thinking about. And then there is other more unusual things. For antidepressants, certain antidepressants can cause increase in blood pressure. Not all antidepressant medications, but like SNRIs, for instance, we think about amphetamines, of course, we mentioned that earlier and several of the treatments we use for ADD and ADHD are problematic unfortunately. We think about other prescribed medications, such as, for instance, we deal with this a lot in the kidney transplant space. People who are on tacrolimus or cyclosporin, they have very difficult to control hypertension and a lot of drug interactions. They're the one group that we actually do treat with beta blockers as one of their first-line antihypertensive medications because we can't often treat them with other agents because they can harm their kidneys or kidney excuse me, single, or they can end up having an adverse interaction with the tacrolimus and creative challenges in managing it. We tend to only use it in that situation that I'm aware of. And then we deal with a lot of cancer therapies that people don't often think about really can cause very severe acute hypertension. American Heart Association put out a scientific statement on management of hypertension in cancer patients. And a huge part of that is all about VEGF inhibitors and tyrosine kinase inhibitors. And how it's incredibly important to be thinking about checking your patient's blood pressures daily initially upon starting these medications because you can end up with a stroke within a few days by how severe your blood pressure can be elevated by one of these agents. And then alternatively, if they're being held, you have to quickly reduce the antihypertensive agents because these are older folks often with more stiffer blood vessels. As soon as you stop one of these agents, it's similar to having preeclampsia go on and then shut off, in terms of the mechanism. You can end up just seeing a very sudden drop in blood pressure as well. My father-in-law actually has renal cell carcinoma and is treated with a VEGF inhibitor, and he ended up developing a stroke because nobody told him to hold your antihypertensive agentMatt: Oh my God. Jordy: -when we're holding your VEGF inhibitor. So, he was off of it for a week because of another adverse effect and developed much worse secondary effect to his antihypertensive medications. So, he's doing okay. He's actually still working full time. He's like a crazy guy. But something that didn't need to happen, it was iatrogenic. This is really common in these patients. I've seen this quite frequently in patients referred to me.
But it's really important because several herbal supplements can worsen HTN or interact with anti-hypertensive agents. So, Ginkgo, ginseng, St. John's wort is concerning because it has a lot of interactions, particularly to black licorice from other countries, from outside the US. Same of whatever that's called. Glycyrrhizic acid.
One that I'm seeing a lot of, I've had like a half a dozen consults for this in the not-so-distant past is tizanidine-induced hypertension. So, tizanidine is a muscle relaxant increasingly being used for chronic pain in the era of we're trying to avoid opioids, of course, and I think it was great that folks were starting to think outside the box to find alternative pain medications. I find a lot of the pain specialists are prescribing tizanidine, particularly for back pain. I've also been seeing it used for some migraine prophylaxis as like a late-line agents in people with refractory migraines. And tizanidine is actually a central alpha agonist just like guanfacine and just like clonidine, and tizanidine is really short-acting. And so, it's often prescribed for multiple times a day, but people might only take it at night to help them sleep, for example. So, what happens is, just like clonidine, your blood pressure is going to lower acutely when you take it. And then if you're primed, if you're somebody with hypertension with stiff blood vessels, somebody a little bit more sympathetically active, you're going to have this huge rebound effect. And I've actually had a couple of patients who've had strokes as a result of that rebound effect.
It was somebody who was taking tizanidine sort of PRN intermittently for their pain and developing paroxysmal hypertension. Then he captured it on 24-hour ambulatory blood pressure monitoring and it's incredible in terms of the breadth of blood pressures, you see, like my patient that I had, one of my examples, their blood pressures went from the 70s/40s after taking it up to the 190s210s/120s after it rebounded.
Does everybody get this who's receiving tizanidine for their hypertension? Not necessarily, but I think that it's something to just be thinking about. I wouldn't stop every patient who's on it who's got reasonably well-controlled hypertension, who's not running into any issues, but if you're running into problems with blood pressure control, I would think about it.
But to be clear, randomized control trial evidence has now shown that switching from hydrochlorothiazide to chlorthalidone doesn't necessarily provide benefit in people with blood pressures in, like the 130s/90s or 80s and otherwise no other major risk factors. But yeah, in my higher-risk patients, I have a low threshold to switch them. It stinks because you do have to take them off of that fixed-dose combination because there are no fixed-dose combinations or there are a couple we'll talk about in the US. But very little options in terms of fixed-dose combinations with chlorthalidone. The reason being hydrochlorothiazide only has a half-life of about 9 hours to up to 12 hours. If you're on it for a long term and actually taking it consistently, chlorthalidone has a half-life of up to 40 hours.
And what about indapamide? Because that one is also a longer-acting thiazide, like diuretic, and I feel like it gets no love. Like it's never mentioned anything I read, but it's around. Is that something people should think about using? Jordy: Yeah, it's another really good option. It's easier because it comes in two doses instead of one like chlorthalidone, you get 1.25 mg or 2.5 mg, so I'll often start it at 1.25 mg and that's a little bit of a step up from hydrochlorothiazide as a typical dosing that most of our patients are taking. And then the 2.5 mg is really a little bit more of a potent dose. So, I'll tend to get a little more bang for my buck with 2.5 mg. So, if I'm not starting it fresh, if I'm switching them from hydrochlorothiazide, I'll actually put them on 2.5 mg of indapamide. It is long-acting, not quite as long-acting as chlorthalidone. Why isn't it used more? I think it's another one because it's not available in any fixed-dose combinations in the US to my knowledge. So, again, it has to be prescribed separately, but a lot of folks prefer prescribing separately. I don't know why it's not used more otherwise. It's really common in Canada. It was used in all the Canadian trials, like HYVET and these other huge trials that the Canadians did, and that was their version of chlorthalidone, but for some reason the US just never bought into it. I really think a lot of all of this has to do with pharmaceutical reps in the 90s when these drugs were first coming widely into use and the fact that they did a really great job of marketing hydrochlorothiazide when it was first being compounded with mixed agents.